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The goal of the current research was to develop VLD-loaded zein protein-based nanoparticles (VLD-ZP NPs) for enhancing their oral hypoglycemic effect, achieving a sustained release profile, and addressing the issues associated with rapid metabolism and side effects. A 2\n                    <jats:sup>3<\/jats:sup>\n                    full factorial design was utilized to assess the influence of independent formulation variables on the observed responses. The independent variables considered were VLD-to-zein weight ratio (X\n                    <jats:sub>1<\/jats:sub>\n                    ), ethanol-to-water volume ratio (X\n                    <jats:sub>2<\/jats:sub>\n                    ), and stirring time (X\n                    <jats:sub>3<\/jats:sub>\n                    ). The dependent responses evaluated were particle size (Ps), zeta potential (Zp), entrapment efficiency (EE), and percent of drug release after 2H (Q\n                    <jats:sub>2H<\/jats:sub>\n                    ) and 8H (Q\n                    <jats:sub>8H<\/jats:sub>\n                    ). The optimized VLD-ZP NPs formula (F04), with a desirability value of 0.94, exhibited a small Ps (149.64\u2009\u00b1\u20091.4nm), low Q\n                    <jats:sub>2H<\/jats:sub>\n                    (23.97\u2009\u00b1\u20092.1%), high Zp (\u2212\u200937.67\u2009\u00b1\u20091.8mV), high EE (68.67\u2009\u00b1\u20092.3%), and sustained Q\n                    <jats:sub>8H<\/jats:sub>\n                    release (62.57\u2009\u00b1\u20092.4%). Further investigations of F04 confirmed sustained drug release, spherical vesicle morphology through TEM, and effective entrapment\n                    <jats:italic>via<\/jats:italic>\n                    DSC and X-ray diffraction.\n                    <jats:italic>In vivo<\/jats:italic>\n                    pharmacokinetic studies revealed that C\n                    <jats:sub>max<\/jats:sub>\n                    and AUC\n                    <jats:sub>0-12H<\/jats:sub>\n                    of F04 were enhanced by 1.25-fold and 1.8-fold compared to the marketed VLD product. Also, t\n                    <jats:sub>1\/2<\/jats:sub>\n                    and MRT were extended by 1.84-fold and 1.56-fold, respectively. These findings indicated improved oral bioavailability and prolonged residence time of VLD. Additionally, the\n                    <jats:italic>in vivo<\/jats:italic>\n                    pharmacodynamic study revealed that F04 provided markedly superior and sustained hypoglycemic effects over the marketed VLD product, with higher R\n                    <jats:sub>max<\/jats:sub>\n                    , longer TR\n                    <jats:sub>\u00bd<\/jats:sub>\n                    , and a 2.8-fold increase in AUC\n                    <jats:sub>(0-24H)<\/jats:sub>\n                    .\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1208\/s12249-025-03300-7","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T18:31:32Z","timestamp":1768501892000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Biopolymeric Zein Protein Nanoparticles for Oral Vildagliptin Delivery: Fabrication, Statistical Optimization, and In Vivo Pharmacokinetics and Pharmacodynamics Insights"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2435-2698","authenticated-orcid":false,"given":"Asmaa","family":"Ashraf Nemr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9722-9631","authenticated-orcid":false,"given":"Abdelhamid","family":"Ibrahim Elshafey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2053-2050","authenticated-orcid":false,"given":"Amir","family":"Ibrahem Mohamed Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0998-5638","authenticated-orcid":false,"given":"Mona Mohamed","family":"Elkhatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7565-301X","authenticated-orcid":false,"given":"Mahmoud","family":"Teaima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0070-1969","authenticated-orcid":false,"given":"Mohamed A.","family":"El-Nabarawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8830-6781","authenticated-orcid":false,"given":"Mai Ahmed","family":"Tawfik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"3300_CR1","doi-asserted-by":"publisher","unstructured":"Sarkar S, Das D, Dutta P, Kalita J, Wann SB, Manna P. 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